Interaction of newly synthesized N-cyclopropylmethyl derivatives of (-)-6 beta-acetylthionormorphine with opioid receptors.

1. Analgesic activities of N-cyclopropylmethyl derivatives of (-)-6 beta-acetylthionormorphine, KT-89 and KT-90 and their interactions with opioid receptors were studied. 2. KT-89 and KT-90, as well as morphine inhibited the twitch response of the guinea-pig ileal preparation to electrical stimulation. Their pD2 values indicated that KT-89 and KT-90 are about 6.5 and 10 times as potent as morphine, respectively. In guinea-pig ileal preparation KT-89 and KT-90 also behaved as a mu-antagonist. 3. In rabbit vas deferens which contains kappa-receptors, these substances inhibited the twitch response to electrical stimulation and were about 6 times as potent as dynorphin. 4. Their effects on specific binding of [3H]naloxone (mu-selective ligand), [3H]ethylketocyclazocine (kappa-selective ligand) and [3H]D-Ala2-D-Leu5-enkephalin (delta-selective ligand) to the synaptosomal fractions from rat brain were tested. Though both drugs had a nonselectively high affinity to mu-, kappa- and delta-receptors, affinities of KT-89 and KT-90 to kappa-receptors were about 6 and 13 times higher than that of morphine, respectively. 5. Analgesic activities of KT-89 and KT-90 were 6 and 10 times as potent as morphine in an acetic acid-induced writhing test, and 4 and 5 times as potent in a pressure test. 6. The present results suggest that KT-89 and KT-90 induced analgesic actions are mediated through an activation of kappa-receptors. Both the drugs acted as delta-receptor antagonists. Further experiments are needed to study effects of their property as a delta-antagonist on analgesic action.